Bioavailability assessment of topical delivery systems: effect of inter-subject variability on relative in vitro deliveries of minoxidil and hydrocortisone from solution and ointment formulations

Abstract

The present study demonstrates that in vitro comparisons of delivery vehicles are reliable as long as one performs the studies on skin samples taken from the same cadaver section of skin. The in vitro rates of delivery of minoxidil and hydrocortisone from an ointment and a propylene glycol/ethanol/water vehicle through skin sections taken from the same and different cadaver abdomens are specifically compared. When tested on skins from 8 human cadavers, the fluxes of minoxidil suspended in the ointment ranged from 0.37 × 10 −5 mg/cm 2/h to 9.2 × 10 −5 mg/cm 2/h, a 25-fold spread, and the fluxes of minoxidil from the propylene glycol/ethanol/water vehicle ranged from 1.25 × 10 −5 mg/cm 2/h to 18.7 × 10 −5 mg/cm 2/h, a 15-fold spread. However, when the ratios of fluxes between these two formulations were calculated for individual subjects, the values ranged from 1.3 to 3.5 (only a 3-fold spread). Four human cadaver sections were used to evaluate the delivery of hydrocortisone. The flux values ranged from 696 to 1335 cpm/cm 2/h for the ointment and 946 to 1291 cpm/cm 2/h for the propylene glycol/ethanol/water vehicle (up to a 2-fold spread). When the ratios of fluxes between these two formulations were calculated for each individual subject, the values ranged from 0.96 to 1.39. The results with these two compounds suggest that even in the unavoidable presence of large inter-subject variations in the cadaver skin, the influence of vehicle on drug delivery performance can be determined. In addition to these findings concerning intra-subject variability, it was observed that the flux of minoxidil from the ointment attains a steady-state after an initial lag period of between 6 and 8 h but steady delivery is not apparent for the minoxidil solution, suggesting that for the solution formulation the thermodynamic activity of. the drug changes markedly as the experiment proceeds. No comparable curvature is seen for the hydrocortisone solution presumably because its thermodynamic activity is little changed during the vehicle's evaporation.